TY - JOUR
T1 - Preclinical evidence that PD1 blockade cooperates with cancer vaccine TEGVAX to elicit regression of established tumors
AU - Fu, Juan
AU - Malm, Ian James
AU - Kadayakkara, Deepak K.
AU - Levitsky, Hy
AU - Pardoll, Drew
AU - Kim, Young J.
PY - 2014/8/1
Y1 - 2014/8/1
N2 - Biomarker studies have shown that expression of the T-cell coregulatory ligand PDL1 on tumor cells correlates with clinical responsiveness to the PD1 antibody nivolumab. Here, we report the findings of a preclinical cancer vaccine study demonstrating vaccine-dependent PDL1 upregulation in the tumor microenvironment. We formulated an IFNγ-inducing cancer vaccine called TEGVAX that combined GM-CSF and multiple Toll-like receptor agonists to increase the number of activated dendritic cells. Treatment of established tumors with TEGVAX retarded tumor growth in a manner associated with enhanced systemic antitumor immunity. Unexpectedly, TEGVAX also upregulated PDL1 expression in the tumor microenvironment, possibly explaining why tumors were not eliminated completely. In support of this likelihood, PDL1 upregulation in this setting relied upon IFNg-expressing tumor-infiltrating CD4+ and CD8 + T cells and administration of a PD1-blocking antibody with TEGVAX elicited complete regression of established tumors. Taken together, our findings provide a mechanistic rationale to combine IFNg-inducing cancer vaccines with immune checkpoint blockade.
AB - Biomarker studies have shown that expression of the T-cell coregulatory ligand PDL1 on tumor cells correlates with clinical responsiveness to the PD1 antibody nivolumab. Here, we report the findings of a preclinical cancer vaccine study demonstrating vaccine-dependent PDL1 upregulation in the tumor microenvironment. We formulated an IFNγ-inducing cancer vaccine called TEGVAX that combined GM-CSF and multiple Toll-like receptor agonists to increase the number of activated dendritic cells. Treatment of established tumors with TEGVAX retarded tumor growth in a manner associated with enhanced systemic antitumor immunity. Unexpectedly, TEGVAX also upregulated PDL1 expression in the tumor microenvironment, possibly explaining why tumors were not eliminated completely. In support of this likelihood, PDL1 upregulation in this setting relied upon IFNg-expressing tumor-infiltrating CD4+ and CD8 + T cells and administration of a PD1-blocking antibody with TEGVAX elicited complete regression of established tumors. Taken together, our findings provide a mechanistic rationale to combine IFNg-inducing cancer vaccines with immune checkpoint blockade.
UR - http://www.scopus.com/inward/record.url?scp=84905457466&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84905457466&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-13-2685
DO - 10.1158/0008-5472.CAN-13-2685
M3 - Article
C2 - 24812273
AN - SCOPUS:84905457466
SN - 0008-5472
VL - 74
SP - 4042
EP - 4052
JO - Cancer Research
JF - Cancer Research
IS - 15
ER -